Preterm birth is the most common cause of death in newborn babies worldwide (Moss et al., 2002). In the US preterm delivery is one of the most significant complications of pregnancy. Approximately 34% of infant mortality is due to preterm delivery in the US (Callaghan et al., 2006). It has a high prevalence rate (11%), and about 40% (>$4 billion) of all infant health care expenditures in the US are related to prematurity.
Infection is the most common cause of preterm delivery and stillbirth globally. In the US infection plays a role in ˜50% of total and 80% of early preterm deliveries (<32 weeks of gestation) (Lamont, 2003; Goldenberg et al., 2000). However, despite being one of the most important maternal-fetal problems, there are no effective prevention strategies or treatments for infection-induced preterm delivery, and there is no thorough understanding of the molecular mechanisms involved.
The traditional conception of preterm delivery has been that of an ordinary pregnancy progressing to term before the fetus is ready for delivery. In recent years this conception has come into question, and physicians are beginning to think of preterm delivery as a disease state caused by pathologies in the fetal/placental unit. It has thus been suggested that preterm delivery be considered a syndrome caused by multiple etiologies but ending in a common pathway (Bernstein, 2000). The present invention relates to one end pathway, namely apoptotic processes (programmed cell death) induced by infection or other injury to fetal/placental tissues.
Up to 80 percent of early preteen births (<32 weeks) are associated with intrauterine infection. Despite the link between intrauterine infection and preterm delivery, antibiotic treatment of women with intrauterine infection is not uniformly protective. In fact, some clinical trials of antibiotic treatment of intrauterine infections have been associated with worse outcomes. These seemingly inconsistent results are likely due to the fact that the apoptotic processes triggered by the infection, rather than the infection itself, are responsible for the increased risk of preterm delivery.
It has been shown that microbial antigen treatment of primary human placenta cells (trophoblasts) and trophoblast cell lines leads to increased rates of apoptosis in these cells. Specifically, the inventors have recently shown that microbial antigens activate apoptotic machinery in the human placental cells (Equils et al., 2006) Moreover, mouse models of intrauterine infection and sepsis suggest that there is increased apoptosis in the placentas and membranes of the animals exposed to microbial antigens. This link between apoptosis, intrauterine infection and preterm delivery, in conjunction the failure of antibiotics to prevent preterm delivery, suggest that increased apoptosis is a factor in preterm delivery. Accordingly, there is a need for treatments that modulate the apoptotic pathway induced by intrauterine infection or other injury, rather than solely treating the infection itself.